1. Field of the Invention
This invention relates to the hydroxamic acid derivatives subsituted by di-tert-butyl(hydroxy)phenylthio residue which may be useful as medicine. More particularly, it relates to the hydroxamic acid derivatives subsituted by di-tert-butyl(hydroxy)phenylthio residue, which inhibit LDL (Low Density Lipoprotein) from being incorporated into macrophages, whereby they may be useful as an anti-arteriosclerosis agent.
Besides, they have also anti-oxidation activities to show preventive activity to oxidation of lipid, ulcer formation, and lipoxygenase action, whereby they may be useful as agent for vessel disorder, anti-asthma agent, anti-diabetes agent, anti-ulcer agent, anti-inflammatory agent, anti-tumor agent, anti-allergy agent, and the like.
2. Description of the Prior Art
Atherosclerosis recognized to be a significant symptom which occurs in an initial stage of arteriosclerosis, in such a manner that lipid material mainly consisting cholesterol moves into the arterial wall accompanied by hyperplasia and consequent sclerosis. Atherosclerosis has been thought not to occur due to a single factor but accumulated factors over a long period of time, such as hypertension, hyperlipemia, excessive cigarette smoking, obesity, diabetes mellitus, hyperuricemia, stress, heredity, lack of exercise, etc. Among those factors, the behavior of cholesterol existing as LDL in blood is noted. What is especially important are penetration of LDL into the arterial wall and the incorporation of LDL into macrophages, and the subsequent accumulation of cholesterol at the wall and the vessel disorder. On the other hand, the following factors are considered to promote the occurrence of atherosclerosis: the increase of blood cholesterol due to the troubles on the incorporation of LDL into liver and the metabolism of LDL in liver, the hydrodynamic state of blood due to the change in the physical properties of red blood cell, the damage of endothelium, the abnormal hyperplasia of the arterial wall and the depression of the lipid utilization in arterial tissues, and the like.
For the drug therapy of atherosclerosis, there have heretofore been used anti-arteriosclerosis agents such as pyridinol carbamate; lipid lowering agents such as chlofibrate, nicotinic acid, alpha-tyroxine and chloestyramine; and antiplatelet agents such as dipyridamole and aspirin, etc. The analogues which have activities of lowering lipids in serum or lipoxygenase inhibitory activities are disclosed in U.S. Pat. Nos. 4,029,812, 4,076,841, 4,078,084, EP 273451, or the like. The hydroxamic acid derivatives which have lipoxygenase inhibitory activity are disclosed in JP. Unexam. Publn. No. 86-257951, JP. Unexam. Publn. No. 86-251640, JP. Unexam. Publn. No. 86-251641, JP. Unexam. Publn. No. 86-251642, JP. Unexam. Publn. No. 88-225340, JP. Unexam. Publn. No. 89-104033, JP. Unexam. Publn. No. 89-153658, EP 279263, or the like. This invention characterized by the hydroxamic acid derivatives having di-tert-butyl(hydroxy)phenylthio moiety is new. GB 2,212,153 is quite relavant to the present invention. However, this generally discloses a certain compound of the present invention while it does not specifically disclose such compound.